Technical Aspects and Development of Transcatheter Aortic Valve Implantation

Aortic stenosis is the most common valve disease requiring surgery or percutaneous treatment. Since the first-in-man implantation in 2002 we have witnessed incredible progress in transcatheter aortic valve implantation (TAVI). In this article, we review the technical aspects of TAVI development with a look at the future. Durability, low thrombogenicity, good hydrodynamics, biocompatibility, low catheter profile, and deployment stability are the attributes of an ideal TAVI device. Two main design types exist—balloon-expandable and self-expanding prostheses. Balloon-expandable prostheses use a cobalt-chromium alloy frame providing high radial strength and radiopacity, while the self-expanding prostheses use a nickel-titanium (Nitinol) alloy frame, which expands to its original shape once unsheathed and heated to the body temperature. The valve is sewn onto the frame and consists of the porcine or bovine pericardium, which is specially treated to prevent calcinations and prolong durability. The lower part of the frame can be covered by polyethylene terephthalate fabric or a pericardial skirt, providing better sealing between the frame and aortic annulus. The main future challenges lie in achieving lower rates of paravalvular leaks and new pacemaker implantations following the procedure, lower delivery system profiles, more precise positioning, longer durability, and a good hemodynamic profile. Patient-specific design and the use of autologous tissue might solve these issues

Aggregation Time Machine: A Platform for the Prediction and Optimization of Long-Term Antibody Stability Using Short-Term Kinetic Analysis

Monoclonal antibodies are the fastest growing class of therapeutics. However, aggregation limits their shelf life and can lead to adverse immune responses. Assessment and optimization of the long-term antibody stability are therefore key challenges in the biologic drug development. Here, we present a platform based on the analysis of temperature-dependent aggregation data that can dramatically shorten the assessment of the long-term aggregation stability and thus accelerate the optimization of antibody formulations. For a set of antibodies used in the therapeutic areas from oncology to rheumatology and osteoporosis, we obtain an accurate prediction of aggregate fractions for up to three years using the data obtained on a much shorter time scale. Significantly, the strategy combining kinetic and thermodynamic analysis not only contributes to a better understanding of the molecular mechanisms of antibody aggregation but has already proven to be very effective in the development and production of biological therapeutics

Computed tomographic perfusion imaging for the prediction of response and survival to transarterial chemoembolization of hepatocellular carcinoma

The purpose of this retrospective cohort study was to evaluate the clinical value of computed tomographic perfusion imaging (CTPI) parameters in predicting the response to treatment and overall survival in patients with hepatocellular carcinoma (HCC) treated with drug-eluting beads transarterial chemoembolization (DEBTACE)

Long-Term Stability Predictions of Therapeutic Monoclonal Antibodies in Solution Using Arrhenius Based Kinetics

Long-term stability of monoclonal antibodies is the key aspect in their development for use as (bio)pharmaceutical products; therefore, possible prediction of long-term stability from accelerated stability studies is of major interest, despite currently regarded as not sufficiently robust. In this work, using combination of accelerated stability studies (up to 6 months) and first order degradation kinetic modelling, we are able to predict long-term stability (up to 3 years) including temperature dependence of changes of multiple quality attributes and for multiple monoclonal antibody formulations. More specifically, we can robustly predict the long-term stability behavior of a protein at the intended storage condition (5°C), based on up to six months data obtained from different temperatures, usually from intended (5°C), accelerated (25°C) and stress conditions (40°C). We have performed stability studies and evaluated the stability data of several mAbs including IgG1, IgG2, IgG4 and fusion proteins and validated our model by overlaying the 95% prediction interval and experimental stability data from up to 36 months. We demonstrated improved robustness, speed and accuracy of kinetic long-term stability prediction as compared to classical linear extrapolation used today, justifying long-term stability prediction and shelf life extrapolation for some biological products such as monoclonal antibodies. More generally, this work aims to contribute towards further development and refinement of the regulatory landscape that will allow extrapolation for biological products during the developmental phase, clinical phase and also in marketing authorization applications, as already established today for small molecules